Malignant neoplasia is the second most common cause of death in the United States behind cardiovascular disease (National Vital Statistics Reports. 2005, 53, 7). New cancer chemotherapeutic agents and methods of care combined with early detection and treatment have been largely responsible for decreases in both the overall incidence of cancer and death rates from all cancers combined (Jemal, A. et al., Cancer. 2004, 101, 4). There remain many cancer patients for whom no or minimally effective therapy exists. Furthermore, cancers that are initially responsive to current therapies may become resistant and increasingly difficult or impossible to treat. There is an unmet need for novel chemotherapeutics with greater efficacy or safety, either as monotherapy or in combination with other chemotherapeutic agents, and such agents with the potential to overcome drug resistance in cancer cells.
The mushroom Omphalotus illudens is a source of the highly toxic sesquiterpenes illudin S and M (1, 2). (See, e.g., McMorris, T. C. et al., J. Am. Chem. Soc. 1963, 85, 831).

These compounds were tested by the National Cancer Institute and were found to possess anti-tumor activity but with a poor therapeutic index. (See, e.g., Kelner, M. J. et al., Cancer Research 1987, 47, 3186). However, certain derivatives of these compounds have shown greatly improved efficacy as anti-tumor agents with a better safety profile. In particular, the derivative irofulven (3) (McMorris, T. C. et al., J. Nat. Prod. 1996, 59, 896) has been extensively investigated and is currently in phase II clinical trials against ovarian, prostate and gastrointestinal cancers, both as a monotherapy (Cvitkovic E. et al., J. Clin. Oncol. 2004, 22, 4766; and Falcon-Lizaraso, S. et al., J. Clin. Oncol. 2004, 22, 333) and in combination with well known anticancer agents. In fact, irofulven has demonstrated clinical activity with an acceptable safety profile in hormone-refractory prostate cancer (Senzer N. et al., Am. J. Clin. Oncol. 2005, 28, 36). Most relevant to clinical applications, irofulven activity is independent of common resistance mechanisms such as the multidrug resistance phenotype, anti-apoptotic bcl-2 over expression, as well as p53 and p21waf1/cip1 mutations (Kelner M. J. et al., Cancer Res., 1995, 55, 4936; Poindessous V. et al., Clin Cancer Res. 2003, 9, 2817; and Herzig M. C. et al., Biochem Pharmacol. 2003, 65, 503).
There exists a continuing need for chemotherapeutic agents that inhibit solid (e.g., tumor) and non-solid, such as hematologic, cancer cell growth and which have an adequate therapeutic index to be effective for in vivo treatment.